Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, and the most aggressive subtype, activated B-cell-like (ABC), kills 60% of patients within three years. One important feature of ABC DLBCL is autocrine signaling by the cytokines IL6 and IL10, which is essential for cancer growth. The molecular mechanisms underlying the cytokine signaling pathway remain undefined and will be a focus of this study. In preliminary results, we identified the constitutively activated kinase downstream of the cytokine pathway as JAK1. Cancer cells require JAK1 activity for survival; JAK1 inhibition by RNA interference or the pharmaceutical inhibitor AZD1480 is lethal to cultured ABC DLBCL cells. As a tyrosine kinase, JAK1 regulates gene expression through phosphorylating STAT3 as well as through a surprising non- canonical mechanism, directly targeting the histone protein H3 for tyrosine 41 phosphorylation (H3Y41p). Genome-wide mapping of this modification identified 2,582 JAK1 target genes. Some of these genes that are induced for expression through H3Y41p are independent of STAT3, including the oncogene MYC and important NF-kB genes MYD88 and IRF4. Given that NF-kB activation is a hallmark of ABC DLBCL and causes auto-secretion of the cytokines IL6 or IL10, JAK1 and NF-kB signaling pathways form a positive feedback loop to promote the survival and proliferation of cancer cells. These findings support the hypothesis that JAK1 regulates gene expression via two complementary pathways to promote cancer cell survival and proliferation, and JAK1 downstream target genes are potential candidates for therapeutic intervention in ABC DLBCL. In fact, the Bruton tyrosine kinase (BTK, upstream of IRF4) inhibitor, Ibrutinib, has been effective in ABC DLBCL. Due to drug resistance, however, Ibrutinib only achieves a temporary remission. The proposed research will test the hypothesis that overcoming acquired resistance to Ibrutinib by combined targeted therapies helps further improve outcomes of ABC DLBCL. Specifically, dual interruption of NF-kB and JAK1 by their inhibitors will be conducted in ABC DLBCL xenograft mouse models as well as in primary patient samples. The goals of the proposed research are to establish a conceptual framework for understanding how JAK1 mediates transcription activation through these two distinct (STAT3-mediated or chromatin targeting) mechanisms, to identify novel molecular targets of JAK1, and to develop a new therapeutic strategy for the disease.